SUMMARY Obesity is a major public health problem which has reached epidemic proportions with rates of about 36% for women in the United States. Worldwide, over 30% of pregnant women are obese. Human epidemiological studies have shown that maternal obesity (MO) increases risks of offspring later life cardiovascular disease (CVD). Evidence suggests that MO leads to offspring cardiac remodeling and dysfunction. However, the pathophysiological and molecular mechanisms underscoring the onset and development of CVD in offspring of obese mothers remain poorly defined. Most studies of adverse effects of MO on developmental challenges and life course outcomes are in polytocous, altricial rodents. For translation to human disease, studies in monotocous precocial species are required. Sheep have an extensive life course physiological and genomic database making them good models for studies of mechanisms of origins of adult CVD. Our preliminary data indicates that cortisol levels are significantly elevated in fetuses and newborns of obese ewes by comparing to control ewes. The compelling body of evidence in many species from many independent laboratories showed that the elevated cortisol level could play a key role in pathophysiological changes of fetal, neonatal and adult offspring heart. Using our sheep facilities which are probably the only remaining USA facility for the necessary pre-pregnancy, pregnancy and life course offspring maintenance for long-term study, we will test the central hypothesis that elevated fetal cortisol level by MO from gestation day75 to newborn leads to altered autophagy and/or mitophagy level in fetal hearts, and RBM39 plays a critical role in mediating this process through co- activation along with cortisol receptors. Two specific aims are proposed to test the hypothesis. Aim 1 will assess autophagy/mitophagy changes in the heart of fetuses of obese mothers. Aim 2 will determine the role of RBM39 in cortisol-induced autophagy and/or mitophagy in fetal hearts of obese mothers. The success of our research using this MO sheep model will provide novel insights into the underlying mechanisms in the onset and development of CVD in offspring of obese mothers, and enable us to find potential new targets for the treatment and prevention of MO-induced cardiac remodeling and CVD later on in life.